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ACC NY Cardiovascular Symposium
Peripheral Vascular Disease:
Watch the Heart and the Brain
Evolving Role of Exercise, ACE-Inhibitors, Interventional and
Surgical Options
Mark A. Creager, M.D
President, American Heart Association
Dartmouth-Hitchcock Heart and Vascular Center
Geisel School of Medicine at Dartmouth
Lebanon, NH
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Conflicts of Interest
• None
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Peripheral Artery Disease (PAD)
• The presence of a stenosis or occlusion in the aorta or arteries of the limbs
• Usually caused by atherosclerosis
• Associated with an increased risk of death, myocardial infarction, and stroke
• May impair walking or cause critical limb ischemia
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Age,
years
Women, % Men, %
HIC LMIC HIC LMIC
25–29 2.70 3.96 2.76 1.21
30–34 3.20 4.46 3.27 1.50
35–39 3.78 5.01 3.88 1.87
40–44 4.47 5.62 4.58 2.33
45–49 5.28 6.31 5.41 2.89
50–54 6.23 7.08 6.38 3.58
55–59 7.33 7.92 7.51 4.43
60–64 8.60 8.87 8.82 5.47
65–69 10.08 9.91 10.33 6.74
70–74 11.77 11.05 12.07 8.28
75–79 13.71 12.32 14.05 10.13
80–84 15.91 13.70 16.30 12.33
85–89 18.38 15.22 18.83 14.94
90–94 21.14 16.87 21.65 17.99
95–99 24.20 18.65 24.77 21.50
Global Prevalence of PAD
– The global burden of PAD is estimated to be 202 million persons
– The prevalence increases with age
– In HIC, the prevalence of PAD is similar between women and men
– In LMIC, the prevalence of PAD was higher in women than men at most ages
Estimated Age-Specific PAD
Prevalence for Women and Men in HIC
and LMIC
Fowkes FG, et al. Lancet. 2013;382(9901):1329-1340.
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Diehm, C. et al. Circulation 2009;120:2053-2061
The German Epidemiological Trial on ABI Study:Event-free Survival by PAD status
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REACH Registry One Year Event Rates for the
Composite of CV Death, MI and Stroke
Steg PG et al,. JAMA 2007;297(11): 1197-1206.
4.5
6.5
5.4
2.2
0
1
2
3
4
5
6
7CADPADCVDRisk Factors
Perc
ent
CAD CVD PAD Risk Factors
The REACH Registry recruited >68,000 outpatients aged ≥45 years
with established CV disease or ≥3 risk factors from 44 countries.
Approximately 25% of the
patients with PAD had a
history of MI, 30% had
angina, 16% had a previous
stroke, and 15% had a
previous TIA
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Reinecke et al. Eur Heart J 2015;36:932-938
Death Amputation
Contemporary PAD Outcomes in Germany
n = 41,882 PAD patients hospitalized during 2009 – 2011Followed until 2013, (mean 1144 days)
7,825 patients were amputated and 10,880 died.
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Physican Use of Secondary Prevention Therapies in PAD
18.7%
0 20% 40% 60% 80%
Statin use
20.8%ACE/ARB use
27.4%Anti-platelettherapy use
34.3%
65.8%
57.5% PAD with CVD
PAD without CVD
p<0.0001*
* Statistical comparison by Chi-square testPande et al., Circulation, 2011
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The Efficacy of Statin TherapyThe Heart Protection Study
Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
Previous MI 23.5 29.4
Other CHD 18.9 24.2
No prior CHD or CBV disease 18.7 23.6
Diabetes 13.8 18.6
All patients 19.8 25.2
1.2 1.40.6 0.4
24% Reduction24% Reduction24% Reduction24% Reduction
((((PPPP<.0001)<.0001)<.0001)<.0001)
Existing diseaseStatin Control
Incidence of events
(n=10,269) (n=10,267) Statin favored Placebo
Risk vs Control
PAD 24.7 30.5
0.8 1.0
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REACH Registry: Statin Therapy and AdverseLimb Outcomes in Patients with PAD
Multivariate modeling
Statin use (Y/N)
(N = 5,861)
Multivariate modeling
Time-varying statin use (N =
5,006)
Multivariate modeling
Propensity analysis
(N = 5,642)
All-cause mortality 0.82 (0.72 – 0.95) P=0.009 0.79 (0.65 – 0.94) P=0.0098 0.96 (0.84 – 1.09) P=0.51
CV mortality 0.83 (0.69 – 0.99) P=0.04 0.78 (0.61 – 0.98) P=0.034 0.90 (0.77 – 1.06) P=0.21
Non-fatal MI 0.89 (0.66 – 1.20) P=0.44 0.80 (0.58 – 1.11) P=0.18 0.69 (0.53 – 0.89) P=0.004
Non-fatal stroke 0.73 (0.57 – 0.93) P=0.013 0.75 (0.57 – 0.97) P=0.029 0.73 (0.59 – 0.92) P=0.006
Worsening claudication or
new CLI
0.82 (0.70 – 0.95) P=0.0087 0.84 (0.72 – 0.99) P=0.037 0.78 (0.68 – 0.90) P=0.0005
New limb revascularization 0.83 (0.72 – 0.95) P=0.0079 0.90 (0.77 – 1.04) P=0.14 0.79 (0.69 – 0.90) P=0.0003
New amputation 0.64 (0.48 – 0.86) P=0.0027 0.60 (0.44 – 0.82) P=0.0014 0.57 (0.43 – 0.74) P<0.0001
Non-fatal stroke 0.73 (0.57 – 0.93) P=0.013 0.75 (0.57 – 0.97) P=0.029 0.73 (0.59 – 0.92) P=0.006
Worsening claudication or
new CLI
0.82 (0.70 – 0.95) P=0.0087 0.84 (0.72 – 0.99) P=0.037 0.78 (0.68 – 0.90) P=0.0005
New limb revascularization 0.83 (0.72 – 0.95) P=0.0079 0.90 (0.77 – 1.04) P=0.14 0.79 (0.69 – 0.90) P=0.0003
New amputation 0.64 (0.48 – 0.86) P=0.0027 0.60 (0.44 – 0.82) P=0.0014 0.57 (0.43 – 0.74) P<0.0001
Kumbhani D J et al. Eur Heart J 2014Days from Randomization
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Atorvastatin in Patients With Claudication and PAD
PFWT=pain-free walking time.*P=.03. No change in ABI over 12 months.
Mohler ER et al. Circulation. 2003;108:1481-1486.
*
Baseline Month 3 Month 6 Month 12
Mean change from baseline
in PFWT (sec)
0
25
50
75
100
125
10 mg
Placebo80 mg
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ACE Inhibitors in PAD
The HOPE Trial
HOPE Study Investigators. N Engl J Med. 2000;342:145-153.
History of CAD 7477
No history of CAD 1820Prior MI 4892
No prior MI 4405CBV disease 1013
No CBV disease 8284Peripheral vascular disease 4051
No peripheral vascular disease 5246Microalbuminuria 1956
No microalbuminuria 7341
No. ofPatients
ReducedReducedReducedReduced IncreasedIncreasedIncreasedIncreasedRelative risk in ramipril group
0.6 0.8 1.0 1.2
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Population RRR (95% CI) P
Qualifying CAD, CVD, or PAD 0.88 (0.77, 0.998) .046
(n=12,153)
Multiple risk factors 1.20 (0.91, 1.59) .20
(n=3,284)
Overall population* 0.93 (0.83, 1.05) .22
(N=15,603)
CHARISMA: Affect of Clopidogrel plus Aspirin vs. Aspirin Alone
on MI, Stroke, or CV Death
0.6 0.8 1.41.2Clopidogrel better Placebo better
1.60.4
Bhatt DL, Fox KA, Hacke W, et al. New England Journal of Medicine, 2006
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CHARISMA: Outcomes in the PAD Cohort
P Cacoub et al., Euopean Heart Jounal, 2009
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TIMI TRA2oP: Effect of Vorapaxar on CV Events in PAD
0%
2%
4%
6%
8%
10%
12%
14%
0 180 360 540 720 900 1080
CV Death, MI, or Stroke
Placebo
Vorapaxar
N = 376711.3%
11.9%
Hazard Ratio 0.94;95% CI (0.78 - 1.14)
p = 0.53
Morrow DA, Braunwald E, Bonaca MP. N Engl J Med. 2012; 366: 1404-1413Days from Randomization
Eve
nt
Ra
te
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0%
1%
2%
3%
4%
5%
0 180 360 540 720 900 1080
Effect of Vorapaxar on Limb Vascular Events in PAD
Hospitalization for Acute Limb Ischemia
Pre-specified, adjudicated
2.3%
3.9%
Hazard Ratio 0.5895% CI 0.39 to 0.86
p = 0.006
PlaceboVorapaxar
N = 3767
Days from randomization
4
3
2
1
5
Event
Rate
(%
)
Bonaca et al Circulation. 2013;127:1522-1529
00 180 360 540 720 900 1080
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0%
5%
10%
15%
20%
25%
0 180 360 540 720 900 1080
Effect of Vorapaxar on Limb Vascular Events
Peripheral Revascularization
Prespecified
18.4%
22.2%
Hazard Ratio 0.84;
95% CI 0.73 to 0.97
p = 0.017
PlaceboVorapaxar
N = 3767
Days from randomization
20
15
10
5
25
Eve
nt
Ra
te
(%)
Bonaca et al Circulation. 2013;127:1522-1529
0
0 180 360 540 720 900 1080
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Treatment of Symptomatic PAD
• Medical Therapy
• Exercise Training
• Revascularization
– Endovascular Intervention vs. Open
– Surgical Revscularizartion
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Effect of Cilostazol on Maximal Walking Distance:
A Meta-analysis
0
20
40
60
Pe
rce
nt
Me
an
Ch
an
ge
fro
m B
ase
lin
e
in M
axi
ma
l W
alk
ing
Dis
tan
ce
**
Cilostazol 100 mg
Cilostazol 50 mg
Placebo
Pentoxifylline
Pande et al., Vasc Med 2010 15: 181
Nine randomized, placebo controlled trials
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Claudication: Exercise vs. Endoluminal Revascularization
The CLEVER Study
Pair-Wise Comparisons
Difference (minutes) P Value
Exercise vs. OMC 4.6 (95% CI, 2.7-6.5) <0.001
Stenting vs. OMC 2.5 (95% CI, 0.6-4.4) 0.02
Exercise vs. Stenting 2.1 (95% CI, 0.0-4.2) 0.04
Peak Walking TimeChange from Baseline to Six (6) Months
Min
ute
s
TP Murphy et al., Circulation, Published online 11.16.11
min
ute
s
n = 22 n = 43 n = 46
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The ERASE TrialEndovascular Revascularization and Supervised Exercise
vs. Supervised Exercise for Intermittent Claudication
Fahkry et al., JAMA. 2015;314(18):1936-1944
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The IRONIC Trial:Improved Walking Distance with an Invasive vs.
Noninvasive Strategy
n =158
Nordanstig J et al. Circulation. 2014;130:939-947
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Nordanstig J et al. Circulation. 2014;130:939-947
The IRONIC Trial:Improved Quality of Life with an Invasive Strategy
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The BASIL StudyAngioplasty vs Bypass Surgery
on Amputation Free Survival in Patients with CLI
BASIL Trial Participants, Lancet, 366:1925, 2005
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• NHLBI-sponsored prospective, randomized, multicenter,
open label superiority trial
• 2,100 patients at 120 clinical sites in United States and Canada
• 4-year trial extending from 2014-2017, with each patient having
minimum of 2 year follow-up
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Thank you!